IBN-9724035 PI: STOLLBERG This research is directed at a better understanding of the molecular events underlying "synaptogenesis" (the formation of synapses during fetal development), which is of fundamental importance because synapses are the conduits through which nerve cells communicate with each other and with other cell types such as muscle fibers. At nerve-muscle synapses the communication depends on the release of acetylcholine from the nerve terminal. This molecule diffuses across a small space between the cells and binds to specialized muscle-cell molecules called "acetylcholine receptors." The binding of acetylcholine to its receptors triggers muscle contraction. Because nerve-muscle synapses must be fast and reliable, the receptors are concentrated in that part of the muscle cell membrane that is adjacent to the nerve terminal. This concentration takes place during fetal development, and many research efforts have been directed at discovering the molecular mechanisms that cause receptors to aggregate at this precise location. This project will examine aggregates of acetylcholine receptors and two related synaptic components at the ultrastructural level. The experiments involve labeling the molecules under study with small gold particles which can be detected using scanning electron microscopy. A sophisticated numerical analysis of label locations is then used to deduce the structure of labeled aggregates to within <1 nanometer. This represents a greater than hundred-fold improvement in resolution over previous experiments with developing receptor aggregates. The successful completion of this work will greatly enhance our understanding of the molecular mechanisms underlying receptor aggregation, and will thus contribute to our understanding of the basic mechanisms by which synapses are formed.
